Bortezomib, Daunorubicin, and Cytarabine in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

Acute Myeloid Leukemia Clinical Trial

Official title:

Dose Escalation and Phase II Study of Bortezomib (IND #58443) Added to Standard Daunorubicin and Cytarabine Therapy for Patients With Previously Untreated Acute Myeloid Leukemia Age 60-75 Years

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00742625
• Other study ID #: NCI-2009-00443
• Secondary ID: NCI-2009-00443CD
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: August 27, 2008
• Last updated: September 4, 2014
• Start date: September 2008
• Est. completion date: December 2012

Study information

• Verified date: June 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies the side effects and best dose of bortezomib when given together with daunorubicin and cytarabine and to see how well it works in treating older patients with previously untreated acute myeloid leukemia. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as daunorubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with combination chemotherapy may kill more cancer cells.

Description:

PRIMARY OBJECTIVES:

I. To define the remission induction response rate (complete response [CR] and CR with incomplete platelet recovery [CRp]) in older patients with previously untreated acute myeloid leukemia treated with induction therapy comprising bortezomib in combination with daunorubicin hydrochloride and cytarabine.

II. To define the maximum tolerated dose of bortezomib when administered in combination with intermediate-dose cytarabine after induction therapy.

SECONDARY OBJECTIVES:

I. To describe the disease-free survival of patients treated with this regimen. II. To describe the overall survival of patients treated with this regimen. III. To evaluate the treatment-related toxicities in these patients.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Doses of bortezomib are escalated during remission consolidation therapy.

REMISSION INDUCTION THERAPY: Remission induction course 1: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11; daunorubicin hydrochloride IV on days 1-3; and cytarabine IV continuously over 168 hours on days 1-7.

After completion of remission induction course 1, patients undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a complete response (CR) or partial response (PR) proceed to remission consolidation therapy. Patients achieving a CR with incomplete platelet recovery (CRp) proceed to remission consolidation therapy after platelet counts recover. Patients with persistent leukemia (>= 20% bone marrow cellularity and >= 5% bone marrow myeloblasts) proceed to remission induction course 2.

REMISSION INDUCTION COURSE 2: Patients receive bortezomib IV over 3-5 seconds on days 1 and 4; daunorubicin hydrochloride IV on days 1 and 2; and cytarabine IV continuously over 120 hours on days 1-5.

After completion of remission induction course 2, patients undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a CR or PR proceed to remission consolidation therapy. Patients achieving a CRp proceed to remission consolidation therapy after platelet counts recover. Patients with residual leukemia who do not meet the criteria for PR are removed from the study.

REMISSION CONSOLIDATION THERAPY: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and intermediate-dose cytarabine IV over 3 hours on days 1-5. Patients then undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a CR or who demonstrate continuing CR receive a second course of remission consolidation therapy beginning 2-4 weeks after blood counts recover.

After completion of study therapy, patients are followed every 2 months for 2 years, every 3 months for 2 years, and then annually for up to 10 years.

Other known NCT identifiers

• NCT01647061

Recruitment information / eligibility

• Status: Completed
• Enrollment: 95
• Est. completion date: December 2012
• Est. primary completion date: July 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 60 Years to 75 Years

Eligibility

Inclusion Criteria:

• Unequivocally histologically confirmed acute myeloid leukemia (AML)

• At least 20% blasts in the bone marrow based on WHO criteria

• No acute promyelocytic leukemia (M3)

• Antecedent hematologic disorder or myelodysplastic syndromes allowed provided the patient did not receive cytotoxic chemotherapy, including azacitidine and decitabine, for their pre-leukemic disorder

• Concurrent enrollment on CALGB-8461 required

• Not pregnant or nursing

• Fertile patients must use effective contraception

• No ataxia, cranial neuropathy, or peripheral neuropathy >= grade 2

• LVEF >= 40% by ECHO or MUGA scan

• No signs or symptoms of congestive heart failure

• DLCO >= 50% (corrected for hemoglobin)

• No prior therapy for leukemia or pre-leukemic disorders, except for the following:

• emergency leukapheresis;

• emergency treatment for hyperleukocytosis with hydroxyurea;

• cranial radiotherapy for CNS leukostasis (one dose only);

• growth factor/cytokine support

• No other concurrent chemotherapy, except for the following:

• I) steroids administered for adrenal failure, hypersensitivity reactions, or septic shock;

• II) hormones administered for non-disease-related conditions (e.g., insulin for diabetes or estrogens or progestins for gynecologic indications)

• No concurrent palliative radiotherapy

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Adult Acute Megakaryoblastic Leukemia (M7)
• Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
• Adult Acute Monoblastic Leukemia (M5a)
• Adult Acute Monocytic Leukemia (M5b)
• Adult Acute Myeloblastic Leukemia With Maturation (M2)
• Adult Acute Myeloblastic Leukemia Without Maturation (M1)
• Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
• Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
• Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
• Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
• Adult Acute Myelomonocytic Leukemia (M4)
• Adult Erythroleukemia (M6a)
• Adult Pure Erythroid Leukemia (M6b)
• Leukemia
• Leukemia, Erythroblastic, Acute
• Leukemia, Megakaryoblastic, Acute
• Leukemia, Monocytic, Acute
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Acute
• Leukemia, Myelomonocytic, Chronic
• Untreated Adult Acute Myeloid Leukemia

Intervention

Drug:
• daunorubicin hydrochloride
Given IV
• cytarabine
Given IV
• bortezomib
Given IV

Locations

Country	Name	City	State
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina	Chapel Hill	North Carolina
United States	University of Chicago	Chicago	Illinois
United States	University of Missouri - Ellis Fischel	Columbia	Missouri
United States	Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center	Columbus	Ohio
United States	Kinston Medical Specialists PA	Kinston	North Carolina
United States	North Shore University Hospital	Manhasset	New York
United States	North Shore-LIJ Health System CCOP	Manhasset	New York
United States	Long Island Jewish Medical Center	New Hyde Park	New York
United States	North Shore-LIJ Health System/Center for Advanced Medicine	New Hyde Park	New York
United States	Mount Sinai Medical Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Florida Hospital	Orlando	Florida
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Lombardi Comprehensive Cancer Center at Georgetown University	Washington	District of Columbia
United States	Washington Hospital Center	Washington	District of Columbia
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Remission Induction Response	Response was calculated according to Revised International Working Group (IWG) criteria for Acute myeloid leukemia (AML); A response was defined as the portion of participants who achieved a complete response (CR) or CR with incomplete platelet recovery(CRp) during induction.; A CR is defined as those with > 20% cellularity of bone marrow biopsy, no presence of extramedullary leukemia for AML, <5 % myeloblast cells for bone marrow with peripheral blood and normal complete blood count (absolute neutrophils > 1000 mL and platelets >= 100,000 mL).; A CRp is defined as a CR except platelets < 100,000 mL without need for transfusion.	2 months	No
Primary	Participants Experiencing a Dose-limiting Toxicity (DLT) of Bortezomib When Administered in Combination With Intermediate-dose Cytarabine	DLTs were considered only during the first cycle of consolidation therapy and included grade 3 or 4 sensory or autonomic neuropathy, persistent grade 4 thrombocytopenia or neutropenia at day 42 in the absence of AML,any grade 4 or 5 nonhematologic toxicity, and any grade 3 nonhematologic toxicity (excluding neuropathy and toxicities secondary to neutropenia and sepsis) that did not resolve to grade 2 by day 42 unless attributable to persistent or recurrent AML. Grade 4 anorexia (requiring total parenteral nutrition) and grade 4 fatigue (requiring bed rest) were not considered DLTs.; Toxicity was graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grading scale is as follows: grade 1: mild; grade 2: moderate; grade 3: Severe; grade 4: Life Threatening; grade 5: Death.	during consolidation cycle 1 (42 days)	Yes
Secondary	Disease-free Survival	Disease-free survival (DFS) was measured as the interval from achievement of CR until relapse or death, regardless of cause. DFS was estimated using the Kaplan Meier method.	Duration of study (up to 10 years)	No
Secondary	Overall Survival	Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method.	Duration of study (up to 10 years)	No